Oral pharmaceutical composition comprising zonisamide and process of preparation thereof

ABSTRACT

The present invention relates to the pharmaceutical composition comprising Zonisamide and one or more pharmaceutically acceptable excipients and also relates to the process for the preparation of the pharmaceutical composition comprising Zonisamide.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International Application No.PCT/IB2018/000901 filed Aug. 18, 2018, which claims priority to Indianprovisional application Serial No. IN201721026411 filed Aug. 19, 2017.Each of which are hereby incorporated by reference in their entireties.

FIELD

The present invention relates, in general, to the pharmaceutical field,and more precisely it relates to a pharmaceutical composition for theoral administration of Zonisamide and to the process for the preparationthereof. In particular, the present invention relates to the oral liquidcomposition comprising Zonisamide.

BACKGROUND

Zonisamide, chemically known as 1,2-benzoxazol-3-ylmethanesulfonamidehaving an empirical formula C₈H₈N₂O₃S and a molecular weight of 212.2gm/mol has a following structural formula:

Zonisamide is a benzisoxazole derivative, originally synthesized inJapan in 1974 during exploratory research on psychiatric drugs, where itwas subsequently identified as having anticonvulsant activity duringscreening. Zonisamide is thought to act through its blocking ofvoltage-dependent sodium channels, reduction of voltage-dependent T-typeinward calcium currents, binding to the gamma-aminobutyric acid(GABA)-benzodiazepine receptor complex, and facilitation of bothdopaminergic and serotonergic neurotransmission. Zonisamide was approvedin Japan in 1989 as both monotherapy and adjunctive therapy for childrenand adults with generalized or partial seizures. Zonisamide was approvedin 2000 in the USA as adjunctive therapy in the treatment of partialseizures in adults with epilepsy. For epilepsy, most studies have usedoral zonisamide in daily doses ranging from 200 to 600 mg/day, dividedin 2 daily doses, adjusted to maintain serum levels of 15 to 40 μg/ml.Zonisamide is also proposed for treatment of other disease like tardivedyskinesia. It is to be sold, when combined with bupropion, under thebrand name empatic for obesity. Zonisamide has been studied for and usedas a migraine preventative medication, and has also been shown to beeffective in some cases of neuropathic pain. It has also been usedoff-label by psychiatrists as a mood stabilizer to treat bipolardepression.

EP 2301537 describe a composition comprising zonisamide or apharmaceutically acceptable salt thereof for use in reducing the weightof an obese subject.

EP 2285374 describe a composition comprising a combination of at leasttwo compounds chosen from the group consisting of zonisamide,dyphylline, tadalafil, argatroban, acamprosate, cinacalcet, terbinafine,cilostazol, baclofen, phenformin, amlodipine and sulfisoxazole, or saltsor prodrugs or derivatives or sustained release formulations thereof,for simultaneous, separate or sequential administration.

EP 2222296 and EP 2164487 describe a pharmaceutical compositioncomprising an AMPA receptor antagonist, Zonisamide and one or morepharmaceutically acceptable carriers. EP1683516 describes a stablepharmaceutical dosage form comprising, in intimate mixture, solidparticulate zonisamide and at least one pharmaceutically acceptableexcipient.

EP1913935 describes a process for preparing a stable zonisamidepharmaceutical composition, comprising subjecting zonisamide to wetgranulation with a granulation liquid to form a granulated mixture asthe stable zonisamide pharmaceutical composition wherein the granulationliquid is selected from purified water, alcohol and mixtures thereof.

EP1656094 describes a method of improving the safety of patientsreceiving zonisamide treatment for epileptic seizures comprisingproviding a patient with a therapeutically effective amount ofzonisamide, and informing the patient that during the course ofzonisamide therapy, if (s)he experiences one or more symptoms chosenfrom the group of abdominal pain, hypovolemia, shock, nausea, anorexia,vomiting, and abdominal distention, to seek immediate medical attention.

EP1503755 describes a method of reducing weight in an overweightsubject, said method comprising administering to an overweight subject apharmaceutical composition comprising zonisamide, in an amount effectiveto reduce weight in said subject, wherein said weight loss issignificant and sustained.

EP1682522 describes a process for the manufacturing of zonisamidecompound.

EP1505967 describes use of a first compound and a second compound in thepreparation of a medicament for treating obesity in a mammal in need ofsuch treatment, wherein said first compound is bupropion, and saidsecond compound is at least one weight-loss promoting anticonvulsant.

EP1040830 describes a medicament for neurodegenerative diseasescomprising zonisamide or an alkali metal salt thereof as an activeingredient.

EP1954241 describes a sustained-release pharmaceutical formulationcomprising, zonisamide; and a retardant excipients, wherein thepharmaceutical formulation has a sustained-release dissolution profilecomprising at least one dissolution characteristic selected from: (a)Less than 70% of the zonisamide in the sustained-release pharmaceuticalformulation is dissolved within a first hour in a standard dissolutiontest, and (b) Less than 75% of the zonisamide in the sustained-releasepharmaceutical formulation is dissolved within a second hour in astandard dissolution test, wherein said pharmaceutical formulationcomprises at least 5% by weight of said retardant excipients. EP1411931describes a method of treating headache in a subject in need of suchtreatment, said method comprising, administering to a subject apharmaceutical composition comprising zonisamide, in an amount effectiveto relieve headache.

Currently Zonisamide is available in oral solid dosage forms likecapsule and tablet. Some patient particularly children and the seriouslyill persons are not able to swallow solid dosage form. Liquid dosageforms are used fairly commonly by young children or the elders who havetrouble swallowing the solid oral dosage forms. Its action is more rapidthan solid dosage forms. Therefore there is a need to develop oralliquid dosage form for Zonisamide.

OBJECT OF THE INVENTION

The principal object of the present invention is to provide an oralliquid pharmaceutical composition for Zonisamide.

A further object of the present invention is to provide a process forthe preparation of the oral liquid pharmaceutical composition ofZonisamide of the present invention.

A further object of the present invention is to provide composition ofZonisamide for use in adjunctive therapy in the treatment of partialseizures in adults with epilepsy.

SUMMARY

Accordingly, the present invention provides a liquid pharmaceuticalcomposition comprising Zonisamide and one or more pharmaceuticallyacceptable excipients selected from the group comprising of suspendingagent, thickening agent, preservatives, buffering agents, sweeteningagents, flavoring agents, vehicles or combinations thereof with improvedstability and palatability.

There is also provided a method of preparing the liquid pharmaceuticalcomposition comprising Zonisamide and one or more pharmaceuticallyacceptable excipients selected from the group comprising suspendingagent, thickening agent, preservatives, buffering agents, sweeteningagents, flavoring agents, vehicles or combinations thereof.

DETAILED DESCRIPTION

Zonisamide, chemically known as 1,2-benzoxazol-3-ylmethanesulfonamidehaving an empirical formula C₈H₈N₂O₃S and a molecular weight of 212.2gm/mol has a following structural formula:

Zonisamide is a benzisoxazole derivative, originally synthesized inJapan in 1974 during exploratory research on psychiatric drugs, where itwas subsequently identified as having anticonvulsant activity duringscreening. Zonisamide is thought to act through its blocking ofvoltage-dependent sodium channels, reduction of voltage-dependent T-typeinward calcium currents, binding to the gamma-aminobutyric acid(GABA)-benzodiazepine receptor complex, and facilitation of bothdopaminergic and serotonergic neurotransmission. Zonisamide was approvedin Japan in 1989 as both monotherapy and adjunctive therapy for childrenand adults with generalized or partial seizures. Zonisamide was approvedin 2000 in the USA as adjunctive therapy in the treatment of partialseizures in adults with epilepsy. For epilepsy, most studies have usedoral Zonisamide in daily doses ranging from 200 to 600 mg/day, dividedin 2 daily doses, adjusted to maintain serum levels of 15 to 40 μg/ml.Zonisamide is also proposed for treatment of other disease like tardivedyskinesia. It is to be sold, when combined with bupropion, under thebrand name empatic for obesity. Zonisamide has been studied for and usedas a migraine preventative medication, and has also been shown to beeffective in some cases of neuropathic pain. It has also been usedoff-label by psychiatrists as a mood stabilizer to treat bipolardepression.

Currently Zonisamide is available in oral solid dosage forms likecapsule and tablet. Some patient particularly children and the seriouslyill persons are not able to swallow solid dosage form. Liquid dosageforms are used fairly commonly by young children or the elders who havetrouble swallowing the solid oral dosage forms. Its action is more rapidthan solid dosage forms. Therefore there is a need to develop oralliquid dosage form for Zonisamide.

Therefore, in one of the embodiments, the present invention provides apharmaceutical composition comprising Zonisamide and one or morepharmaceutically acceptable excipients.

In one of the further embodiments, the pharmaceutical compositioncomprises Zonisamide and one or more pharmaceutically acceptableexcipients selected from the group comprising of suspending agent,thickening agent, preservatives, buffering agents, sweetening agents,flavouring agents, vehicles or combinations thereof.

In one of the further embodiments, the pharmaceutical compositioncomprises Zonisamide and one or more suspending agent, one or morethickening agent, one or more preservatives, one or more bufferingagents, one or more sweetening agents, one or more flavouring agents andone or more vehicles or combination thereof.

In one of the preferred embodiments, the pharmaceutical compositioncomprises Zonisamide, a suspending agent, a thickening agent, apreservative, a buffering agent, a sweetening agent, a flavouring agent,a vehicle or combination thereof.

In one of the preferred embodiments, the pharmaceutical composition is aliquid pharmaceutical composition.

In one of the preferred embodiments, the liquid pharmaceuticalcomposition is suitable for oral administration.

In one of the further embodiments, the pharmaceutical composition isuseful for the manufacture of a medicament.

In one of the further embodiments, the pharmaceutical composition isuseful as a medicament.

In one of the further embodiments, the pharmaceutical composition isuseful for the manufacture of a medicament in the treatment of partialseizures in adults with epilepsy.

Suspending agents referred in the present invention are the compoundswhich are added to increase the viscosity of the solution, which isnecessary to prevent sedimentation of the suspended particles.Suspending agents also act as thickening agents therefore sometimes theyare also referred as thickening agents as well. Examples of suitablesuspending agent are but not limited to sodium alginate,methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, CMC, Na-CMC, microcrystalline cellulose,tragacanth, xanthan gum, bentonite, carageenan, guar gum, colloidalsilicon dioxide. The preferred suspending agent is MCC & Na-CMCDispersion and xanthan gum.

Buffering agents referred in the present invention are the compoundswhich provide stability and pH control to the pharmaceuticalformulations. Examples of suitable buffering agents are but not limitedto sodium acetate, sodium citrate, ammonium sulfate, sodium phosphate,disodium hydrogen phosphate, potassium citrate, citric acid monohydrate,trisodium citrate dihydrate. The preferred buffering agents are citricacid monohydrate and trisodium citrate dihydrate.

Preservatives referred in the present invention are the compounds whichare included in pharmaceutical dosage form to prevent the growth ofmicroorganisms during the product's manufacture and shelf life. Examplesof the suitable preservatives are but not limited to benzyl alcohol,chloro-butanol, chloro-cresol, alkyl esters of paraben, phenol, phenylethanol, benzoic acid, potassium sorbate, sodium benzoate etc. andantimicrobial solvents like propylene glycol, chloroform etc. Thepreferred preservative is sodium benzoate.

Sweetening agents referred in the present invention are the compoundsthat impart sweetness and improve patient compliance through tastemasking. Examples of the suitable sweetening agents are but not limitedto sucralose, sucrose, liquid glucose, glycerol, sorbitol, maltitol,saccharin sodium and aspartame. The preferred sweetening agent issucralose.

Flavouring agents referred in the present invention are the compoundswhich are added to increase patient acceptance of the drug by maskingthe specific taste sensations. Examples of suitable flavouring agent arebut not limited to essential oils including peppermint oil, orange oil,and lemon oil etc. or can be selected from fruit flavour, e.g.peppermint flavour, strawberry flavour, tutti fruit flavour etc. Thepreferred flavouring agent is strawberry flavour.

Vehicles referred in the present invention are the liquid bases whichcarry drug and other excipients in dissolved or dispersed state and canbe selected from either aqueous vehicles or oily vehicles. Examples ofsuitable aqueous vehicles are but not limited to purified water,hydro-alcoholic, polyhydric alcohols and buffers, while suitableexamples of oily vehicles are but not limited to vegetable oils, mineraloils, organic oily bases or emulsified bases. The preferred aqueousvehicle is purified water.

Although zonisamide has good wettability, in some embodiments thepharmaceutical composition may benefit from the addition of a wettingagent. Thus, the pharmaceutical composition, particularly thesuspensions, may further include a wetting agent. In some embodiments,the wetting agent is selected from alcohol, glycerin, propylene glycol,polyethylene glycol, mineral oil, benzalkonium chloride, benzethoniumchloride, cetylpyridinium chloride, docusate sodium, nonoxynol 9,octoxynol, poloxamer, poloxamer 124, poloxamer 188, 237, 338, 407,polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 10oleyl ether, polyoxyl 20 cetylstearyl ether, polyoxyl 40 stearate,polysorbate 20, polysorbate 40, polysorbate 25 60, polysorbate 80,sodium lauryl sulfate, sorbitan monolaurate, sorbitan monooleate,sorbitan monopalmitate, sorbitan monostearate, tyloxapol, and acombination thereof. In some embodiments, the wetting agent is glycerin.

Some embodiments provide a pharmaceutical composition in the form of asuspension for oral delivery comprising zonisamide; water; a suspendingagent; and a buffering agent in an amount sufficient to make thecomposition pH about 3 to about 6. In some embodiments, the suspendingagent is xanthan gum at about 3 to about 3.5 mg/mL, although anysuitable suspending agent may be used. In some embodiments, thebuffering agent is citric acid monohydrate or disodium hydrogenphosphate. Some embodiments further comprise microcrystallinecellulose/sodium carboxymethylcellulose. Some embodiments, mayoptionally include up to 25 mg/mL glycerin.

In some embodiments, the suspension comprises an active pharmaceuticalingredient which is selected zonisamide; a suspending agent which isabout 2 to about 3.5 mg/mL xanthan gum; a buffering agent which iscitric acid monohydrate or disodium hydrogen phosphate; 0 to 25 mg/mLglycerin; and microcrystalline cellulose/sodium carboxymethylcellulose.

In one of the further embodiments, the present invention providesprocess for the preparation of the pharmaceutical composition comprisingZonisamide and one or more pharmaceutically acceptable excipientsselected from the group comprising of suspending agent, thickeningagent, preservatives, buffering agents, sweetening agents, flavouringagents, vehicles or combinations thereof.

In one of the preferred embodiments, the present invention providesprocess for the preparation of the pharmaceutical composition comprisingZonisamide by dissolving the preservative, buffering agent andsweetening agent in one part of water while adding the suspending agent,flavouring agent and Zonisamide active ingredient in other part ofwater, and making up the final volume to required quantity.

In one of the preferred embodiments, the pharmaceutical composition hasa pH in between 3.5 and 5.0. In one of the further preferredembodiments, the pharmaceutical composition has a particle sizedistribution of Zonisamide of D10-13.0 μm, D50-53.0 μm and D90-131.0 μm.

Some embodiments provide a pharmaceutical composition in the form of asuspension for oral delivery comprising zonisamide; water; a suspendingagent; a buffering agent; and one or more of a wetting agent and abinder/filler.

In some embodiments, the wetting agent is selected from alcohol,glycerin, propylene glycol, polyethylene glycol, mineral oil,benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride,docusate sodium, nonoxynol 9, octoxynol, poloxamer, poloxamer 124,poloxamer 188, 237, 338, 407, polyoxyl 35 castor oil, polyoxyl 40hydrogenated castor oil, polyoxyl 10 oleyl ether, polyoxyl 20cetylstearyl ether, polyoxyl 40 stearate, polysorbate 20, polysorbate40, polysorbate 25 60, polysorbate 80, sodium lauryl sulfate, sorbitanmonolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitanmonostearate, tyloxapol, and a combination thereof. In some embodiments,the wetting agent is glycerin.

In some embodiments, the binder/filler is selected from one or morebinders or fillers selected from acacia, agar, alginic acid, carmellosesodium, dextrin, veegum or gel white, gellan gum, sodium alginate,hydroxypropyl starch, maltodextrin, modified starch, pectin, potassiumalginate, polyvinyl pyrrolidone, carboxymethyl cellulose or an alkalimetal salt thereof, microcrystalline cellulose, bentonite, colloidalsilicon dioxide, microcrystalline cellulose/sodiumcarboxymethylcellulose, and any combination thereof. In someembodiments, the binder/filler is microcrystalline cellulose/sodiumcarboxymethylcellulose.

Some embodiments provide a pharmaceutical composition in the form of asuspension for oral delivery comprising zonisamide; water; a suspendingagent; a buffering agent; and one or more of a wetting agent and abinder/filler. In some instances, the buffering agent is present toyield a pH of about 3 to about 8.

In some embodiments, the suspending agent is selected from gelatin,crosslinked polyacrylic acid, polymethacrylic acid, polyhydroxyethylmethacrylic acid, hydroxypropyl methyl cellulose, polyethylene glycol,sodium carboxymethyl cellulose, hyaluronic acid, chitosan,polycarbophil, pectin, copolymers of dextran, polyacrylamide, acacia,copolymer of caprolactone and ethylene oxide, carbopol 934, tragacanth,eudragit, polyvinyl pyrrolidone, polyacrylate and polyacrylate copolymerresins, celluloses and cellulose derivatives for example methyl-, ethyl-and propyl celluloses; hydroxyalkyl-celluloses, hydroxyl propylcelluloses, hydroxylpropylalkyl celluloses and the like includingxanthan gum, polyvinyl resins, polyethylene glycol, polyethylene oxide,sorbitol, sucrose, xylitol, dextrose, fructose, maltitol, sugar, sodiumalginate, or a combination thereof.

Some embodiments further include one or more binders or fillers selectedfrom acacia, agar, alginic acid, carmellose sodium, dextrin, veegum orgel white, gellan gum, sodium alginate, hydroxypropyl starch,maltodextrin, modified starch, pectin, potassium alginate, polyvinylpyrrolidone, carboxymethyl cellulose or an alkali metal salt thereof,microcrystalline cellulose, bentonite, colloidal silicon dioxide,microcrystalline cellulose/sodium carboxymethylcellulose and anycombination thereof.

In some embodiments, the buffering agent is acetate, amino acids,ammonium sulfate, benzoate, bicarbonate, borate, citrate, citric acidmonohydrate, disodium hydrogen phosphate, glutamate, lactate, meglumine,potassium citrate, sodium acetate, sodium citrate, sodium phosphate,sulfate, tartrate, triethanolamine, TRIS, trisodium citrate dehydrate,and any combination thereof.

Some embodiments provide a pharmaceutical composition in the form of asuspension for oral delivery comprising zonisamide; water; a suspendingagent; and a buffering agent in an amount sufficient to make thecomposition pH about 3 to about 6. In some embodiments the activepharmaceutical ingredient is selected from zonisamide, and primodone. Insome embodiments, the suspending agent is xanthan gum at about 3 toabout 3.5 mg/mL, although any suitable suspending agent may be used. Insome embodiments, the buffering agent is citric acid monohydrate ordisodium hydrogen phosphate. Some embodiments further comprisemicrocrystalline cellulose/sodium carboxymethylcellulose. Someembodiments may include up to 25 mg/mL glycerin.

In some embodiments, the suspension comprises zonisamide; a suspendingagent which is about 2 to about 3.5 mg/mL xanthan gum; a buffering agentwhich is citric acid monohydrate or disodium hydrogen phosphate; 0 to 25mg/mL glycerin; and microcrystalline cellulose/sodiumcarboxymethylcellulose.

Some embodiments provide a pharmaceutical composition in the form of asuspension for oral delivery comprising an active pharmaceuticalingredient; water; a suspending agent; a stabilizing amount of wettingagent; and a buffering agent in an amount sufficient to make thecomposition pH about 3 to about 6.

Other embodiments will be apparent from this specification withoutdeparting from the scope and spirit of this disclosure.

EXAMPLES

The pharmaceutical composition of the present invention is explained inmore detail with reference to the following examples. These examples areprovided by way of illustration only and should not be construed aslimit to the scope of the claims in any manner.

Example-1: A Liquid Oral Pharmaceutical Composition ComprisingZonisamide

TABLE 1 ZONISAMIDE LIQUID COMPOSITION Ingredients mg/ml Zonisamide20.00  Carboxymethylcellulose Sodium Dispersion) 20.00  Sodium benzoate2.00 Xanthan gum 3.50 Citric acid monohydrate pH 4-5 Tri-sodium citratedihydrate pH 4-5 Sucralose 2.00 Strawberry flavour 0.10 Purified waterQ.S to 1.0 ml

Method of Preparation: The process for the preparation of the liquidcomposition of Zonisamide involves dissolving required quantities ofsodium benzoate, citric acid monohydrate, tri-sodium citrate andsucralose in purified water, followed by dispersing required quantitiesof Microcrystalline Cellulose & Carboxymethylcellulose SodiumDispersion, xanthan gum, Zonisamide and Strawberry flavour separately inpurified water, mixing both the mixtures, homogenizing it and making upthe final volume to the required quantity of batch size with purifiedwater.

Those who are skilled in the art can understand that variations in theabove described process for the preparation of liquid compositions ofthe present invention can be adopted which are well within the skills ofthe skilled artisan. One can change sequences of the steps in the abovementioned process for the purposes of suitability and conveniencewithout affecting the quality and characteristics of the resultingproduct.

Those who are reasonably skilled in the art can easily understand thatsimilar liquid formulations using Zonisamide with other suitableexcipients, mentioned in the foregoing paragraphs may be prepared in theabove mentioned formula using above mentioned processes for thepreparation. Such other examples of compositions and processes ofpreparation thereof are also within the ambit of the invention disclosedand claimed in the present application.

Example 2: Stability Studies of the Pharmaceutical Composition Preparedin Example 1

The oral liquid pharmaceutical composition prepared according to Example1 exhibits unexpected stability profile when tested after one (1), three(3) and six (6) months under the conditions 40° C./25% RH and 25° C./40%RH. The liquid composition according to the present invention possessvery less amount of impurities and highest degree of purity. The resultsof the stability tests conducted are summarized in the table below.

TABLE 2 STABILITY STUDY RESULTS OF ZONISAMIDE LIQUID COMPOSITION OFEXAMPLE 1 Results 40° C./25% 25° C./40% RH RH Parameters Initial 1 month3 months 3 months Description White to Off Complies Complies Complieswhite suspension pH 4.32 4.18 4.30 4.30 Assay of 97.2  102.3   101.3  101.2   Zonisamide (%) Impurity A ND ND ND ND Unknown 0.06 0.06 0.060.06 Impurities (%) Total 0.07 0.08 0.09 0.10 Impurities (%) ND = NotDetected

Example 3: Zonisamide Suspension

A pharmaceutical composition in the form of a suspension for oraldelivery comprises zonisamide; water; a suspending agent; and abuffering agent in an amount sufficient to make the composition pH about3 to about 6. Exemplary compositions are discussed below:

TABLE 3 ZONISAMIDE ORAL SUSPENSION Prototype Sr. Role of Formula No.Ingredients Ingredients % w/v (mg/mL) 1 Zonisamide Active 2 20 2Microcrystalline Suspending 2 20.00 cellulose and agentCarboxymethylcellulose sodium 3 Sucralose Sweetening 0.2 2.00 agent 4Xanthan gum Suspending 0.35 3.50 agent 5 Sodium Benzoate Preservatives0.1 1.00 6 Citric Acid monohydrate Buffering 0.3719 3.72 agent 7Tri-Sodium Buffering 0.3592 3.59 Citrate Di-hydrate agent 8 Strawberryflavor Flavoring 0.01 0.10 agent 9 water Vehicle q.s to 100 ml q.s to 1ml 1.0% active may also be used with the remaining excipient'sconcentration is same

Example 4: Stability Studies of the Pharmaceutical Composition Preparedin Example 1

The oral liquid pharmaceutical composition prepared according to Example1 exhibits an unexpected stability profile when tested after one (1),three (3) and six (6) months under the conditions 40° C./25% RH and 25°C./40% RH. The liquid composition according to the present inventionpossess very less amount of impurities and highest degree of purity. Theresults of the stability tests conducted are summarized in the tablebelow.

TABLE 4 Initial 40/25-3M 25/40-3M 40/25-6M 25/40-6M 1 Description Whiteto White to White to White to White to offwhite offwhite offwhiteoffwhite offwhite suspension suspension suspension suspension suspension2 PH 4.5 4.2 4.3 4.4 4.4 3 Assay of zonisamide 100.9 101.90% 100.50%102.40% 101.70% Assay of sodium benzoate 89.8 100.90%  94.60% 101.40% 99.80% 4 Impurity A ND ND ND ND 0.01 Single max impurity 0.05 0.06 0.060.05 0.05 Total impurities 0.05 0.06 0.07 0.05 0.05

Methods of treatment. The pharmaceutical compositions disclosed hereinare useful to treat a variety of conditions, diseases, disorders, orother ailments. In some embodiments, the solutions are meant to mimictheir solid form counterparts, providing the same effectiveness in thesame dose. In each case, the method of treating the condition, disease,disorder or other ailment comprises administering the suspension to apatient in need of such treatment to provide a desired ortherapeutically acceptable dose of the active pharmaceutical ingredient.

The methods disclosed are for the treatment of a disease or a conditionthat can be treated by the active pharmaceutical ingredient in thesolution. The method comprises administering to a patient, such ashuman, an effective dosage amount of a liquid pharmaceutical compositioncomprising the active pharmaceutical ingredient and one or morepharmaceutically acceptable excipients or additives as disclosed anddescribed herein.

“Effective dosage amount” as used herein with respect to, for exampleliquid pharmaceutical compositions of the present invention shall meanthat dosage that provides the specific pharmacological response forwhich the active pharmaceutical ingredient administered in a significantnumber of subjects in need of such treatment. It is emphasized that“effective dosage amount”, administered to a particular subject in aparticular instance will not always be effective in treating thediseases described herein, even though such dosage is deemed a“effective dosage amount” by those skilled in the art.

The liquid pharmaceutical compositions of the present invention areproposed to have unexpectedly dramatic dissolution profiles. Rapiddissolution of an administered active agent is preferable, as fasterdissolution generally leads to greater bioavailability and faster onsetof action. To improve the dissolution profile and bioavailability of theactive it would be useful to increase dissolution of the active used sothat it could attain a level close to 100% dissolution of the drugsubstance.

The liquid pharmaceutical compositions of the present inventioncomprising the active pharmaceutical ingredient or salt thereof orderivative thereof, exhibit improved or comparable pharmacokineticprofiles as compared to marketed or known compositions of the sameactive pharmaceutical ingredient or salt or derivative thereof. Forexample, the Cmax and/or AUC of the liquid pharmaceutical compositionsof disclosed herein can be greater than or substantially equal to theCmax and/or AUC for known or marketed compositions, e.g. solidformulations, administered at the same dose. In addition, the Tmax ofthe liquid compositions of the present invention can be lower than orsubstantially equal to that obtained for a known or marketedcompositions, administered at the same dose. In addition, combinationsof an improved or comparable Cmax, AUC and Tmax profile can be exhibitedby the liquid compositions of the invention, as compared to known ormarketed compositions. In further aspects, the liquid compositions ofthe present invention may result in minimal different absorption levelswhen administered under fed as compared to fasting conditions.

The liquid compositions exhibit in comparative pharmacokinetic testingwith marketed or known formulations, administered at the same dose, aTmax not greater than about 90%, not greater than about 80%, not greaterthan about 70%, not greater than about 60%, not greater than about 50%,not greater than about 30%, not greater than about 25%, not greater thanabout 20%, not greater than about 15%, not greater than about 10%, ornot greater than about 5% of the Tmax exhibited by the marketed or knownformulation.

In some embodiments, the liquid compositions exhibit in comparativepharmacokinetic testing with marketed or known formulation, administeredat the same dose, a Cmax which is at least about 50%, at least about100%, at least about 200%, at least about 300%, at least about 400%, atleast about 500%, at least about 600%, at least about 700%, at leastabout 800%, at least about 900%, at least about 1000%, at least about1100%, at least about 1200%, at least about 1300%, at least about 1400%,at least about 1500%, at least about 1600%, at least about 1700%, atleast about 1800%, or at least about 1900% greater than the Cmaxexhibited by the marketed or known formulation.

In one of the further aspects, the liquid compositions of the presentinvention exhibit in comparative pharmacokinetic testing with marketedor known formulation, administered at the same dose, an AUC which is atleast about 25%, at least about 50%, at least about 75%, at least about100%, at least about 125%, at least about 150%, at least about 175%, atleast about 200%, at least about 225%, at least about 250%, at leastabout 275%, at least about 300%, at least about 350%, at least about400%, at least about 450%, at least about 500%, at least about 550%, atleast about 600%, at least about 750%, at least about 700%, at leastabout 750%, at least about 800%, at least about 850%, at least about900%, at least about 950%, at least about 1000%, at least about 1050%,at least about 1100%, at least about 1150%, or at least about 1200%greater than the AUC exhibited by the marketed or known formulation.

In some embodiments, the Tmax of the active pharmaceutical ingredient orsalt thereof used for the preparation of the liquid compositionaccording to the present invention, when assayed in the plasma of themammalian subject, is less than about 6 to about 8 hours. In otheraspects of the invention, the Tmax of the active or salt thereof is lessthan about 6 hours, less than about 5 hours, less than about 4 hours,less than about 3 hours, less than about 2 hours, less than about 1hour, or less than about 30 minutes after administration.

In some aspects, the liquid compositions exhibit improved or comparablebioavailability as compared to known or marketed compositions.

The liquid pharmaceutical compositions of the present invention aresuitable for use in the industry.

It should be understood that various changes and modifications to thepresently preferred embodiments, examples and processes described hereinwill be apparent to those skilled in the art. Such changes andmodifications can be made without departing from the spirit and scope ofthe present subject matter and without diminishing its intendedadvantages. It is therefore intended that such changes and modificationsbe covered by the appended claims.

1. A liquid oral pharmaceutical suspension, comprising: zonisamide in anamount of about 20 mg/mL; a suspending agent; one or more vehicles; andone or more pharmaceutically acceptable excipients, wherein the one ormore pharmaceutically acceptable excipients comprise one or morebuffering agents; wherein the liquid oral pharmaceutical suspension hasa pH of 3.5 to 5.0, wherein the liquid oral pharmaceutical suspension isstable for at least 6 months when stored at 40° C. and 25% relativehumidity.
 2. The liquid oral pharmaceutical suspension of claim 1,wherein the suspending agent comprises sodium alginate, methylcellulose,hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, carboxymethylcellulose (CMC), sodiumcarboxymethylcellulose (Na-CMC), microcrystalline cellulose, tragacanth,xanthan gum, bentonite, carageenan, guar gum, colloidal silicon dioxide,or any combination thereof.
 3. The liquid oral pharmaceutical suspensionof claim 1, wherein the suspending agent comprises sodium alginate,methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, carboxymethylcellulose (CMC), sodiumcarboxymethylcellulose (Na-CMC), microcrystalline cellulose, tragacanth,xanthan gum, or any combination thereof.
 4. The liquid oralpharmaceutical suspension of claim 1, wherein the suspending agentcomprises gelatin, crosslinked polyacrylic acid, polymethacrylic acid,polyhydroxyethyl methacrylic acid, hydroxypropyl methyl cellulose,microcrystalline cellulose, sodium carboxymethylcellulose, hyaluronicacid, chitosan, polycarbophil, pectin, copolymers of dextran,polyacrylamide, acacia, copolymer of caprolactone and ethylene oxide,carbopol 934, tragacanth, eudragit, polyvinyl pyrrolidone, polyacrylateand polyacrylate copolymer resins, hydroxyalkyl-celluloses, xanthan gum,polyvinyl resins, polyethylene glycol, sodium alginate, or anycombination thereof.
 5. The liquid oral pharmaceutical suspension ofclaim 1, wherein the suspending agent is present in the liquid oralpharmaceutical suspension at about 3 mg/mL to about 3.5 mg/mL.
 6. Theliquid oral pharmaceutical suspension of claim 1, wherein the one ormore buffering agents are selected from the group consisting of sodiumacetate, sodium citrate, ammonium sulfate, sodium phosphate, disodiumhydrogen phosphate, potassium citrate, citric acid monohydrate,trisodium citrate dihydrate, and any combination thereof.
 7. The liquidoral pharmaceutical suspension of claim 1, wherein the one or morebuffering agents comprise citric acid monohydrate or tri-sodium citratedihydrate.
 8. The liquid oral pharmaceutical suspension of claim 1,further comprising one or more sweetening agents, one or more flavoringagents, or any combination thereof.
 9. The liquid oral pharmaceuticalsuspension of claim 8, wherein the one or more sweetening agents areselected from the group consisting of sucralose, sucrose, glycerol,liquid glucose, sorbitol, maltitol, saccharin sodium, aspartame, and anycombination thereof.
 10. The liquid oral pharmaceutical suspension ofclaim 1, wherein the one or more vehicles are aqueous vehicles selectedfrom the group consisting of purified water, hydro-alcoholic, apolyhydric alcohol, and any combination thereof.
 11. The liquid oralpharmaceutical suspension of claim 1, wherein the one or more vehiclesconsist of water.
 12. The liquid oral pharmaceutical suspension of claim1, wherein the liquid oral pharmaceutical suspension has a single maximpurity of 0.06% or less and total impurities of 0.10% or less.
 13. Theliquid oral pharmaceutical suspension of claim 1, wherein the liquidoral pharmaceutical suspension exhibits less than 0.05% of impurity Aand less than 0.25% of total impurity.
 14. A method of treating seizuresin a subject in need thereof, comprising administering to the subject aliquid oral pharmaceutical suspension comprising: zonisamide in anamount of about 20 mg/mL; a suspending agent; one or more vehicles; andone or more pharmaceutically acceptable excipients, wherein the one ormore pharmaceutically acceptable excipients comprise one or morebuffering agents; wherein the liquid oral pharmaceutical suspension hasa pH of 3.5 to 5.0, wherein the liquid oral pharmaceutical suspension isstable for at least 6 months when stored at 40° C. and 25% relativehumidity.
 15. The method of claim 14, wherein the subject has troubleswallowing a solid oral dosage form.
 16. The method of claim 14, whereinthe liquid oral pharmaceutical suspension is used as an adjunctivetherapy in the treatment of partial seizures in adults with epilepsy.17. The method of claim 14, wherein the suspending agent comprisessodium alginate, methylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose,carboxymethylcellulose (CMC), sodium carboxymethylcellulose (Na-CMC),microcrystalline cellulose, tragacanth, xanthan gum, or any combinationthereof.
 18. The method of claim 14, wherein the suspending agent ispresent in the liquid oral pharmaceutical suspension at about 3 mg/mL toabout 3.5 mg/mL.
 19. The method of claim 14, wherein the one or morebuffering agents are selected from the group consisting of sodiumacetate, sodium citrate, ammonium sulfate, sodium phosphate, disodiumhydrogen phosphate, potassium citrate, citric acid monohydrate,trisodium citrate dihydrate, and any combination thereof.
 20. The methodof claim 14, wherein the one or more buffering agents comprise citricacid monohydrate or tri-sodium citrate dihydrate.
 21. The method ofclaim 14, wherein the liquid oral pharmaceutical suspension furthercomprising one or more sweetening agents, one or more flavoring agents,or any combination thereof.
 22. The method of claim 21, wherein the oneor more sweetening agents are selected from the group consisting ofsucralose, sucrose, glycerol, liquid glucose, sorbitol, maltitol,saccharin sodium, aspartame, and any combination thereof
 23. The methodof claim 14, wherein the one or more vehicles are aqueous vehiclesselected from the group consisting of purified water, hydro-alcoholic, apolyhydric alcohol, and any combination thereof.
 24. The method of claim14, wherein the one or more vehicles consist of water.
 25. The method ofclaim 14, wherein the liquid oral pharmaceutical suspension has a singlemax impurity of 0.06% or less and total impurities of 0.10% or less. 26.The method of claim 14, wherein the liquid oral pharmaceuticalsuspension exhibits less than 0.05% of impurity A and less than 0.25% oftotal impurity.